Prognostic relevance of preoperative circulating CD8-positive lymphocytes in the urinary bladder recurrence of urothelial carcinoma

Lin, Chih‐Wei; Tung, Chun Liang; Tsai, Yuh Shyan; Shen, Cheng; Jou, Yeong Chin; Yu, Min; Wu, Shu Fen

doi:10.1016/j.urolonc.2010.08.009

Cited by 15 publications

(12 citation statements)

References 24 publications

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“…The prognostic significance of serum levels of proinflammatory mediators such as IL-6, CRP and TNFalpha has been demonstrated in multiple cancers [ 22 , 23 ]. CD8 + T cell count was assessed as a blood marker using flow cytometry in one study [ 24 ]. Authors observed that peripheral blood CD8 + T cell count was inversely correlated to tumour infiltration with CD8 + T cells ( r 2 = 0.63, p < 0.0001).…”

Section: Discussionmentioning

confidence: 99%

Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

et al. 2018

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Background and ObjectiveRecurrence of non-muscle invasive bladder cancer (NMIBC) after initial management occurs in 60–70% of patients. Predictive criteria for recurrence remain only clinical and pathological. The aim of this study was to investigate the prognostic significance of the proportion of checkpoint HLA-G’s receptor ILT2-expressing peripheral CD8+ T cells.ResultsThe proportion of CD4+ILT2+and CD8+ILT2+ T cells was not increased in NMIBC compared to controls. However, a strong association was found between recurrence and CD8+ILT2+ T cell population levels (p = 0.0006). Two-year recurrence-free survival was 83% in patients with less than 18% CD8+ILT2+ T cells, 39% in the intermediary group, and 12% in patients with more than 46% CD8+ILT2+ T cells. Multivariate analyses demonstrated that the proportion of CD8+ILT2+ T cells was an independent predictive factor for recurrence. Adding CD8+ILT2+ T cells population level to clinical variables increased the predictive accuracy of the model by 4.5%.Materials and MethodsAll patients treated for NMIBC between 2012 and 2014 were included prospectively. Blood samples, tumor and clinico-pathological characteristics were collected. HLA-G expression was measured using IHC, and CD8+ILT2+ T cell levels using flow cytometry. Association between HLA-G and CD8+ILT2+ T cell population levels with NMIBC risk of recurrence was investigated using Cox regression analyses. Prediction was measured using the concordance index statistic.ConclusionsWe demonstrated a strong association between the proportion of circulating CD8+ILT2+ T cells and NMIBC risk of recurrence. Gain in prediction was substantial. If externally validated, such immunological marker could be integrated to predict NMIBC recurrence.

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Section: Discussionmentioning

confidence: 99%

Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

et al. 2018

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“…In a cohort of 69 patients with urothelial carcinoma, Sharma et al emphasized in patients with muscle-invasive or advanced urothelial tumors that higher numbers of CD8 + TILs within the tumor (≥8 per high power field) is a favorable prognostic factor for disease-free survival and overall survival [ 26 ]. Our previous study had demonstrated that preoperative circulating CD8 + lymphocytes inversely correlated with CD8 + TILs and that urothelial tumor patients with higher number of preoperative CD8 + circulating lymphocytes had shorter recurrence-free survival than did those with lower ones [ 27 ]. Several tumor-derived immunosuppressive factors have been postulated to play an important role in malignant progression, including VEGF, IL-10, transforming growth factor-beta (TGF-β), prostaglandin E 2 , and so on [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…As for the significance of CD8-positive tumor-infiltrating lymphocytes (CD8 + TILs), the average number was manually determined from 10 random 0.0328-mm 2 digital images captured under high power field (×320). All counts were repeated 3 times by the same pathologist, and the average of the repeat counts was used for statistical analyses [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation

et al. 2016

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Hypoxia-inducible factor-1α (HIF-1α) can control a transcriptional factor forkhead box P3 (Foxp3) protein expression in T lymphocyte differentiation through proteasome-mediated degradation. In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1α degradation. We first demonstrated that Foxp3 expression positively correlates with the metastatic potential in T24 cells and can increase the expression of HIF-1α-target genes, such as vascular endothelial growth factor (VEGF) and glucose transporter (GLUT). Foxp3 protein can bind with HIF-1α, particularly under hypoxia. In vivo ubiquination assay demonstrated that Foxp3 can decrease HIF-1α degradation in a dose-dependent manner. Knocking-down of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression. Thirty-three of 145 (22.8 %) bladder tumors exhibit Foxp3 expression. Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients (p = 0.032), associated with less number of intratumoral CD8+ lymphocyte. The metaanalysis from 2 published datasets showed Foxp3 expression is positively associated with GLUT−4, −9, and VEGF-A, B-, D expression. This reverse post-translational regulation of HIF-1α protein by Foxp3 provides a new potential target for developing new therapeutic strategy for bladder cancer.

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“…This implies that tumour recruitment of B cells, helper T cells, and regulatory T cells is mainly governed by local factors irrespective of the systemic levels, whereas a component of recruitment of CD8+ cytotoxic cells results simply from reflecting levels available in the circulation. The conclusion regarding CD8+ cells is supported by a similar positive correlation in oral squamous cell carcinoma, although in this case CD4+ helper cells also correlated significantly [30], but contrasts with no correlation in cancers of the larynx [31] and a significant negative correlation in urothelial carcinoma recurrences [32]. Two reports comment on the correlation for T regulatory cells, both finding positive correlations, in cancers of the larynx [31] or in 17 cases of triple-negative breast cancer [29].…”

Section: Discussionmentioning

confidence: 75%

Levels of different subtypes of tumour-infiltrating lymphocytes correlate with each other, with matched circulating lymphocytes, and with survival in breast cancer

Verma

Hanby

Horgan

et al. 2020

Breast Cancer Res Treat

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Purpose Breast cancer tumour-infiltrating lymphocytes associate with clinico-pathological factors, including survival, although the literature includes many conflicting findings. Our aim was to assess these associations for key lymphocyte subtypes and in different tumour compartments, to determine whether these provide differential correlations and could, therefore, explain published inconsistencies. Uniquely, we also examine whether infiltrating levels merely reflect systemic lymphocyte levels or whether local factors are predominant in recruitment. Methods Immunohistochemistry was used to detect tumour-infiltrating CD20+ (B), CD4+ (helper T), CD8+ (cytotoxic T) and FoxP3+ (regulatory T) cells in breast cancers from 62 patients, with quantification in tumour stroma, tumour cell nests, and tumour margins. Levels were analysed with respect to clinico-pathological characteristics and matched circulating levels (determined by flow-cytometry). Results CD4+ lymphocytes were the most prevalent subtype in tumour stroma and at tumour edge and CD8+ lymphocytes were most prevalent in tumour nests; FoxP3+ lymphocytes were rarest in all compartments. High grade or hormone receptor negative tumours generally had significantly increased lymphocytes, especially in tumour stroma. Only intra-tumoural levels of CD8+ lymphocytes correlated significantly with matched circulating levels (p < 0.03), suggesting that recruitment is mainly unrelated to systemic activity. High levels of stromal CD4+ and CD20+ cells associated with improved survival in hormone receptor negative cases (p < 0.04), while tumour nest CD8+ and FoxP3+ cells associated with poor survival in hormone receptor positives (p < 0.005). Conclusions Lymphocyte subtype and location define differential impacts on tumour biology, therefore, roles of tumourinfiltrating lymphocytes will only be unravelled through thorough analyses that take this into account.

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Prognostic relevance of preoperative circulating CD8-positive lymphocytes in the urinary bladder recurrence of urothelial carcinoma

Cited by 15 publications

References 24 publications

Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation

Levels of different subtypes of tumour-infiltrating lymphocytes correlate with each other, with matched circulating lymphocytes, and with survival in breast cancer

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